1. Field of the Invention
This invention relates to novel benzopyranylpyrrolinone derivatives that are smooth muscle relaxants, and are thus useful as agents in the treatment of essential and pulmonary hypertension, congestive heart failure, angina, smooth muscle spasm, in particular cerebro-vasospasm, cardiac arrhythmia, stroke, dysmenorrhea, renal failure, peripheral vascular occlusive disease, unstable bladder and urinary retention, nocturnal asthma, and gastrointestinal disorders, in particular irritable bowel syndrome. Other indications include treatment of baldness.
2. Related Disclosures
Benzopyran derivatives are disclosed in the patent literature as having blood pressure lowering activity. For example see U.S. Pat. Nos. 4,048,317 and 4,647,670, European Patent Application Nos. 076,075 and 172,352, and G.B. No. 1,548,222. A typical example is found in U.S. Pat. No. 4,446,113, which discloses a broad range of compounds having antihypertensive activity which are of the formula: ##STR2## wherein: One of R.sub.1 and R.sub.2 is hydrogen and the other is selected from the class of alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, alkylsulphinyl, alkylsulphonyl, alkoxysulphinyl, alkoxysulphonyl, alkoxycarbonylamino, alkylcarbonylamino, or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two alkyl groups, or alkylsulphinylamino, alkylsulphonylamino, alkoxysulphinylamino or alkoxysulphonylamino or ethylenyl terminally substituted by alkylcarbonyl, nitro or cyano, or --C(alkyl)NOH or C(alkyl)NNH.sub.2, the alkyl groups or alkyl moieties of alkyl-containing groups having from 1 to 6 carbon atoms;
one of R.sub.3 and R.sub.4 is hydrogen or alkyl having from 1 to 4 carbon atoms and the other is alkyl having from 1 to 4 carbon atoms, or R.sub.3 and R.sub.4 together with the carbon atom to which they are attached are spiroalkyl having from 3 to 6 carbon atoms; PA1 R.sub.5 is hydrogen, alkyl having from 1 to 3 carbon atoms or acyl having from 1 to 8 carbon atoms, and PA1 n is 1 or 2, the lactam group being trans to the OR.sub.5 group. PA1 R.sub.2 and R.sub.3 are independently hydrogen or lower alkyl; and PA1 R.sub.4 is alkyl; alkenyl; phenyl or phenyl-lower-alkyl in which any phenyl group may be optionally substituted with one or two substituents chosen from lower alkyl, lower alkoxy, halo, trifluoromethyl and hydroxy; --(CH.sub.2).sub.m OR.sub.2 or --(CH.sub.2).sub.m N(R.sub.2).sub.2 ; wherein m is an integer of 1-5 and R.sub.2 is as defined above; PA1 or a pharmaceutically acceptable ester thereof. PA1 (i) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; PA1 (ii) inhibiting the disease, i.e., arresting its development; or PA1 (iii) relieving the disease, i.e., causing regression of the disease.
Similar compounds bearing a hydroxy group on the pyrrolidin-2-one ring are disclosed in EP No. 274,821.
In the search for new drugs to treat a specific disease state a desirable goal is to find a class of compounds that effectively treat that disease state at lower dose levels than allowed by existing therapy, and/or are effective over a longer period of time. Compounds that are effective at low dose levels generally have a better therapeutic ratio, i.e. separate the desired activity from any undesired side effects, and compounds that are effective over a longer period of time eliminate the need for frequent (and inconvenient) administration of the drug.
It has now surprisingly been found that a structurally distinct class of benzopyran compounds has superior smooth muscle relaxant properties, in particular antihypertensive activity. This class of benzopyran compounds is characterized by the presence of a 3-pyrrolin-2-one ring substituted at the 4-position by an ether group. These compounds have been found to be more active and/or longer acting than those compounds previously known in the benzopyranpyrrolidin-2-one series.